7-methyl-16-methylene-delta4-estrene derivatives



United States Patent Ofifice 3,300,521

Patented Jan. 24, 1967 3 300 521 methyl-16 methylene-17a ethinyl17,8-hydroxy-estrene 7 4 their 3-oxo-derivatives and esters thereof.

DERIVATIVES The new compounds can be prepared by known meth- Georg Annerand Peter Wieland, Basel, Switzerland, ods. Advantageously, theprocedure is such that assignors to Ciba Corporation, New York, N.Y., a5 (a) In compounds of the Formula II corporation of Delaware 0 NoDrawing. Filed Sept. 1, 1964, Ser. No. 393,753 I Claims priority,application Switzerland, Sept. 11, 1963,

11,223/63; June 9, 1964, 7,528/64 I 7 Claims. Cl. 260397.4) 10 cm Thepresent invention provides a process for the preparation of newmethylene-steroids of the Forumla I H3 R: their S-hydroxy derivatives ofthe ketals, enol esters, enoI L-Rz 15 ethers, esters or ethers of thecorresponding 3-oxo or 3- r 7 hydroxy compounds, the 17-ox0 group isreduced to forn- CH9 7 a 17,8-hydroxyl group, if necessary, with thesimultaneous introduction of a lower saturated or unsaturated aliphatirhydrocarbon radical in 170L-POSltlOIl. 20 (b) In compounds of theFormula III in which R represents two hydrogen atoms or an oxo group, Rrepresents a free, esterified or etherified hydroxyl group, R representsa hydrogen atom or a lower saturated or unsaturated aliphatichydrocarbon radical and R represents a hydrogen atom or a methyl group.

By esterified hydroxyl group is meant more especially (III a acidradical an aliphatic, alicyclic, araliphatic 0r their 3 -hydroxyderivatives or the ketals, enol esters, enol aromatic carboxylic acidcontaining at most 20: callbon 3O ethers, esters or ethers of thecorresponding 3-oxo or 3 atoms, for mp the acid radical of formic acid,hydroxy compounds, the l6-oxo group is replaced by z methylcarbonicacid, acetic acid, trifluoroacetic acid, trithylene group, ormethylacetic acid, propionic acid, succinic acid, caproic (6) Compoundsof h F l IV acid, decanoic acid, undecenoic acid, hexahydrobenzoic Racid, cyclopentylpropi-onic acid, phenylpropionic acid, Li benzoic acidand furane carboxylic acid. I 3

By etherified hydroxyl group is meant more especially R4 =CH2 thetetrahydropyranyloxy group, a lower alkoxy, a-alkoxyalkoxy,a-alkoxy-cycloalkoxy, a-alkenyloxy, a-cycloal- 4O kenyloxy ora-hydroxyor -a1kanoyloxy-B-halogen-alkoxy 0; group, for example, amethoxy, ethoxy, propoxy, methoxy- (IV ITIBthOXY, y' y, Y-P P Y-( arereacted with a methyl magnesium halide and the addi- Y- Y-( Y- Y I P Y,ytion compounds obtained hydrolysed, 3-ketals, 3-enoi Y Y Yi -(D-W Y-( yp y y esters 3 enol ethers 3-esters or 3-ethers that may be oby y-fl- 0TvL-acetoxy-fi-tfichloTethoxy a tained are hydrolysed to form 3-oxo or3-hydroxy com- P- pounds and the 3-hydroxy compounds obtained are de- ASlower Saturated of unsaturated aliphatic hydfocarhydrogenated to the3-ketones or in these compounds the boll radicals there y be mentioned,for example, lower su-bstituent in position 3 is eliminated and, ifdesired alkyl radicals Such as methyl, y P PY and P PY 17,8-hydroxycompounds that are obtained are esterifiec radicals, lower al'kenylradicals such as vinyl, allyl and or h ifi methallyl radicals, and loweralkinyl radicals such as Th reduction f h 17- compgunds a be ef ethinyland p p y radicals, and the corresponding halofected, for example,either with a complex light-meta genated radicals, for p thetfifll-lc'l'omtitlflylethinY1 hydride, especially an alkali metal boronor aluminiun -P- The term as Used in COIlIleXiOH With hydride, forexample, lithium or sodium boron hydride drocarbon radicals both in theforegoing and hereinafter li hi l i i h d id or lithi tri-tertiary-butmqrefers to radicals having not more than 7 carbon atoms aluminium hydrideor by means of a metal derivative in the hainv especially a Grignardcompound or an alkali metal de-Thenew15'mthy1ene-andr0$tene$aHd-BSUBIICSPOSSGSS rivative such as alithium or sodium derivative, of Valuable pharmacological p p In thetest animal, lower saturated or unsaturated aliphatic hydrocarbon theyexhibit a high anabolic-androgen quotient, and, espe- For the saidreactions there are used the suitable solvents cially the3-unsu'bstituted Not-alkinyl compounds, als especially ethers such asdiethyl ether, tetrahydrofurane high gestagemc and antigonadotropicactivity. They can dioxane, glycol dimethyl ether or polyglycol ether.The

therefor be used as anabolic agents, gestagens and 0v111- introductionof a lower alkinyl radical in l7a-position i: ation inhibitors. They arealso suitable for use as interalso carried out, for example, in such amanner that 2 mediate products in the preparation of medicaments. loweralkyne, for example, acetylene, dissolved, for ex Compounds that arespecially valuable are those of the ample, in a lower alkanol such asethanol, butanol 01 Formula I in which R represents two hydrogen atomstertiary pentanol, or one of the aforementioned ethers or 0x0, Rrepresents a free or esterified hydroxyl group, especially glycoldimethyl ether, is allowed to act on the R represents a lower alkyl,alkenyl or alkynyl group, and 17-oxo compound in the presence of analcoholate, to; R represents a hydrogen atom, for example, A-7a:17aexample, a lower alkali metal alkanolate such as sodiumdimethyl-16-methylene-17/3 hydroxy-estre-ne and A -17etethylate orsodium tertiary amylate.

The conversion of the l6-oxo compounds into the deiired 16-methylenecompounds can be carried out, for example, according to Wittigsprocedure by reaction with .ower trialkylphosphoniutn-methylides ortriarylphosphiim-methylides such as triphenylphosphonium-methylides, )rby reaction with ketene in the presence of a Lewis acid ;uch as borontrifluoride etherate, and decarboxylation of :he resulting spirolactone.

The introduction of the methyl group into compounds of the formula IV isadvantageously performed with methyl magnesium bromide or iodide in thepresence of a catalyst, especially a copper salt, for example a halide9r acetate, such as copper-I-chloride or copper-II-acetate. Solventssuitable for this reaction are especially ethers, for example one of theabove mentioned ethers. The addition product obtained is hydrolysed inthe known manner, for example by treatment with water or advan-:ageously with aqueous ammonium salt solutions, e.g., ammonium chloridesolutions.

When 3-ketals, 3-enol esters, 3-enol ethers, S-esters or 3-ethers areobtained as reaction products they can be converted into thecorresponding 3-ketones or 3 hydrxycompounds by known methods, forexample, by acidic or alkaline hydrolysis or, as the case may be, byhydrogenolysis; for example by means of dilute acetic acid, hydrochloricacid or perchloric acid, sodium or potassium hydroxide, carbonate,methylate, ethylate or borohydride.

S-hydroxy compounds that may be obtained are de hydrogenated to thecorresponding 3-ketones by known methods, for example according toOppenauers method or by means of derivatives of hexavalent chromium,such as chromium trioxide or tertiary butyl chromate.

3-thioketals that may be obtained can be converted into compoundsunsubstituted in position 3 in a manner in itself known, for example, bytreatment with a nickel catalyst, for example, Raney nickel, in anorganic solvent, for example, in one of the aforementioned alcohols orethers, or with an alkali metal or alkaline earth metal such as lithium,sodium, potassium or calcium in liquid ammonia and/or a lower aliphaticamine, for example, diethylamine or ethylenediamine, if desired, in thepresence of the last-mentioned ethers. 3-ketones that may be obtainedcan be converted into 3-thioketals by reaction with a lower aliphaticmercaptan or thioglycol such as methyl-, ethylor propyl-mercaptan orethylene, 1:2- or 1:3-propylene-dithiol and then split as indicated.

The l7 3-hydroxy group in the products of the invention can beesterified or etherified by known methods. The esterification is carriedout, for example, by reacting the 17fi-hydroxy compounds with reactivefunctional derivatives of the acids mentioned above, especially theiranhydrides or halides. In order to prepare the tetrahydropyranyl-ethers,dihydropyrane is allowed to act on the compounds in the presence of anacid catalyst such as para-toluene-sulphonic acid, phosphorousoxychloride or pyridine-hydrochloride. When the l7 8-hydroxy compoundsare reacted with ketals or acetals, especially dimethyl ketals ordiethyl ketals or dimethyl acetals or diethyl acetals of simple ketones,for example, acetone, methylethylketone, cyclopentanone orcyclohexanone, or aldehydes, for example, acetaldehyde orpropionaldehyde, mixed acetals or ketals are obtained bytransacetalization. When heated, these are converted into enol etherswith elimination of alcohol. When a l7-hydr0xy compound is treated withchloral, a hemiacetal is formed whose free hydroxyl group can beesterified in known manner, for example, acetylated or propionylated.

The invention further includes any variant of the present process inwhich an intermediate obtainable at any stage of the process is used asstarting material and any remaining steps are carried out or the processis discontinued at any stage thereof, or in which a starting material isformed under the reaction conditions or is used in the form of a salt.

The compounds used as starting materials can be prepared from theappropriate A -3-oxo-17-hydroxy-an drostadienes or A-3-oxo-l7-hydroxy-estradienes unsubstituted in positions 7 and 16 or theesters thereof. A -3-oxo-7a-methyl-17-hydroxy-androstenes or A B-OX0-7a-methyl-17-hydroxy-estrenes are obtained by treatment withmethylmagnesium iodide in the presence of cuprous chloride or cupricacetate and subsequent hydrolysis. These can be converted by knownmethods into the corresponding B-ketals, for example, theabove-mentioned thioketals or corresponding oxygen-containing ketals,enol esters or enol ethers, for example, enol esters of theabove-mentioned carboxylic acids or enol ethers of lower aliphaticalcohols, and then oxidized to form the corresponding l7-ketones, forexample, with compounds of hexavalent chromium such as chromiumtrioxide.

These can be converted into l7-hydroxy-l6-ketones in known manner, forexample, via the l7-enolacylates and their epoxides. If desired, thel7-hydroxy-l6-ketones can be converted into Not-substituted compounds ofthe formula III after ketalization of the oxo groups present, oxidationof the 17-hydroxy group, introduction of a hydrocarbon radial in17DL-pOSltlOII and, if desired or required, elimination of thesubstituent in position 3 at any step.

The compounds of the Formulas II and IV are obtained from the 17-ketocompounds unsubstituted in position 16, for example, by the Mannichreaction, that is to say, by reaction of the keto compounds withform-aldehyde or with a substance yielding formaldehyde, for example,paraformaldehyde, anda secondary amine, for example, a low erdialkylamine or alkylene-amine, for example, dimethylamine,diethylamine, pyrrolidine or piperidine or a salt thereof, forexample,'the hydrochloride. The resulting Mannich base or its salt,especially that of a Lewis acid, for example, the borontrifiuoridecomplex thereof, can be split in known manner to form the desired16-metl1ylene compound either directly or according to Hoffmann byquaternation of the Mannich base and subsequent degradation of thequaternary ammonium group.

However, the introduction of a l6-methylene group into 17-ketonecompounds unsubstituted in position 16 can also be carried out stepwise.In this process the 17- ketone can first be converted into thecorresponding 16- hydroxymethylene compound by aldol condensation, forexample, with a formic acid ester, especially a low formic acidalkylester such as formic acid ethyl ester. The 16- hydroxymethylenecompound is then reacted with a secondary amine, for example, one ofthose mentioned above, the resulting secondary aminomethylene compound(enamine) is reduced, for example, with a complex aluminium hydride suchas lithium aluminium hydride or lithium-tritertiary butoxy-aluminiumhydride, advantageously in an ether such as diethyl ether ortetrahydrofuran, to form the above-mentioned Mannich base, which canthen be converted into the desired 16-methylene compound in the mannerdescribed.

The introduction of the methylene group into the 16- position can alsobe achieved by oxalic ester condensation with 17-ketones and treatmentof the condensation product with formaldehyde under basic conditions.

It is advantageous to use those starting materials that yield the finalproducts that are described above as being specially valuable.

The new methylene steroids can be used as medicaments, for example, inthe form of pharmaceutical preparations containing the said compounds inadmixture with an inorganic or organic, solid or liquid pharmaceuticalexcipient suitable for enteral or parenteral administration. Suitableexcipients are substances that do not react with the new compounds, forexample, water, gelatine, lactose, starch,

tablets, dragees or capsules, or in liquid form solutions, suspensionsor emulsions. They may be sterilized and/ or contain assistants such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure or buffers. Theymay also contain other therapeutically valuable substances. Thepharmaceutical preparations are prepared by conventional methods andcontain the new methylene steroids, for example, in an amount of0.005-50% by weight or 05-50 milligrams per single dose, for example,per tablet or ampoule.

The new compounds can also be used in veterinary medicine, for example,in one of the above-mentioned forms or in the form of feedstuffs orfeedstuff additives; the usual extenders, diluents or feedstuffs areused.

The following examples illustrate the invention without, however,limiting it.

Example 1 A mixture comprising 18 grams of methyl iodide in 20 millitresof ether, is added dropwise, while stirring to 1.5 grams of lithium in50 millilitres of ether in a stream of nitrogen. When the reaction isfinished, the reaction solution is forced with nitrogen through a spunglass filter into a flask filled with nitrogen while washing with 50millilitres of ether. To the solution of methyl-lithium thus freed fromunreacted lithium are then added 2.9 grams of A-7a-methyl-16-methylene-17-oxo-estrene in a nitrogen stream, whilestirring, and with subsequent washing with 25 millilitres of ether. 16hours later, an ice-methanol mixture with 7.5 millilitres of saturatedsodium sulphate solution containing 0.75 millilitre of 0.1N-sodium-thiosulphate solution is added to the reaction mixture whilecooling. After the addition of water and extracting three times withbenzene the organic solutions are washed four times with water, dried,and then evaporated in vacuo. The residue is chromatographed on 90 gramsof alumina (activity II), whereby the A -7a:17a-dimethyl-16-methylene-17,8-hydroxy-estrene that is formed is eluted with 1:9 and 1:4benzene-petroleum ether mixtures. 1.77 grams thereof melting at 122 to123.5 C. are obtained therefrom by recrystallization from a mixture ofmethylene chloride and ether. 190 milligrams of the same compound can beobtained by concentrating the mother liquor. Optical rotation [a] =57(c.=1.0 48 in chloroform). IR spectrum bands (methylene hloride) at2.77,u. (hydroxyl) and 6.04 11. (double bonds).

The starting material used can be prepared as follows:

A mixture comprising 5 grams of A -7u-methyl-17-oxoestrene, 3 grams ofparaformaldehyde, 10 grams of dimethylamine hydrochloride and 50millilitres of isoamyl alcohol is boiled for 2 hours in a stream ofnitrogen at an oil bath temperature of 150 C. The reaction mixture isthen allowed to stand in a freezing mixture for 3 /2 hours, 30millilitres of N-hydrochloric acid are added, and the mixture is thensuction-filtered through a glass frit while washing with water, coldisoamylalcohol and water. The filter residue is dissolved in methylenechloride, the methylene chloride solution is dried with sodium sulphateand then evaporated in vacuo. By recrystallizing the residue from amixture comprising methylene chloride, ether and pentane, 1.21 grams ofA -7a-methyl-16-methylene 17-oxo-estrene melting at 149.5 to 154.5 C.are obtained. Further recrystallization from the same solvent mixtureraises the melting point to 150 to 155.5 C. UV extinction in rectifiedspirit: e ,,=9250. IR spectrum bands (methylene chloride) at 5.79(16-ketone) and 6.19 (conjugated double bond).

The filtrate obtained above is extracted with ether three timeswhereupon the ethereal solutions are Washed with 0.1 N-hydrochloric acidand water, dried, evaporated in vacuo, and the residue is combined withthe mother liquor of the 1.21 grams of the A-7a-methyl-1-6-methylene-17-oxo-estrene obtained above (residue A). The

aqueous phases are combined, sodium carbonate is added until an alkalinereaction is obtained, and then extracted three times with ether. Theorganic solutions are washed with water, dried, and evaporated in vacuo,and the residue, which comprises crude A-7ot-methyl-l6-dimethylamino-methyl-17-oxo-estrene, is dissolved in 15millilitres of pyridine and 15 millilitres of acetic anhydride, and thesolution is then heated for 2 hours at 100 C. The reaction mixture isthen evaporated in vacuo and the residue is filtered in a benzenesolution through 50 grams of aluminium oxide (activity II) while washingwith 700 millilitres of benzene. The filtrate obtained after evaporationis recrystallized from a mixture comprising methylene chloride, etherand pentane with the use of Carboraflin and there are obtained a further865 milligrams of A -7u-methyl-16 methylene 17-oxo-estrene. The motherliquor is combined with the residue A obtained above and the mixture ischromatographed on grams of alumina (activity II). The fractionsobtained from 1:9, 1:4 and 1:1 mixtures of benzene and petroleum etherare recrystallized from a mixture comprising methylene chloride, etherand pentane and there are obtained a further 895 milligrams of A-7wmethyll6-methylene-17-oxo-estrene. The total yield is thus 2.97grams.

Example 2 A mixture comprising 3.1 grams of A -7a-methyl-16-methylene-17-oxo-estrene, 20 millilitres of toluene and 280 millilitresof ether is saturated with acetylene gas at 0 C. 60 millilitres of a 1.8N solution of sodium-t-amylate in tertiary-amylalcohol-toluene (123.42)are added dropwise at a temperature between -10 and 0 C. in the courseof 20 minutes, and then acetylene gas is conducted through at 0 to 3 C.for 15 hours. The reaction mixture is then poured into 400 millilitresof ammonium chloride solution of 20% strength at a temperature of 5 C.After a good shaking, the aqueous layer is separated, extracted withether and the organic solutions are washed with ice-cold ammoniumchloride solution. The organic solutions are evaporated in a waterjetvacuum, the residue is dried and then chromatographed on grams ofalumina (activity II) whereby A -7vt-methyl 16-methylene l7a-ethinyl17fl-hydroxyestrene is obtained; M.P. 7578, optical rotation [a] =+4(c.=0.9*69 in chloroform).

Example 3 A mixture of 25 grams of methyl iodide and 20 ml. of ether isallowed to flow slowly, with stirring, into a suspension of 2 grams oflithium in 50 ml. of ether. To remove any uncomsumed lithium theresulting mixture is pressed with nitrogen through a glass wool filterinto a second flask and rinsed twice with 25 ml. of ether each time. Theresulting methyl lithium solution is treated with stirring in a currentof nitrogen with 2.28 grams of A -3fl-acetoxy-7a-methyl16-methylene-17-oxoestrene and rinsed with 25 ml. of ether. After 16hours, the reaction mixture, while being cooled with a mixture of iceand methanol, is treated slowly with 10 ml. of saturated sodium sulphatesolution, extracted twice with benzene, washed with water, dried and theextract evaporated in vacuo.

The resulting crude A-35:17B-dihydroxy-7azl7wdimethyl-16-methylene-estnene is dissolved inml. of toluene and 36 ml. of cyclohexanone; 36 ml. of the solvent arethen distilled off, the concentrate treated with a solution of 1.8 gramsof aluminium isopropylate in 36 ml. of toluene, and the batch boiled fortwo hours in a current of nitrogen. The reaction mixture is then pouredon to a dilute Rochelle salt solution and extracted with ether. Theextract is washed with dilute Rochelle salt solution and water, driedand evaporated in vacuo; the residue is dried for a short time in a highvacuum at 90 C. to remove high-boiling constituents. The

residue is chromatographed on 15 grams of alumina (activity II), thefractions eluted with benzene and recrystallized from a mixture ofmethylene chloride and ether, to yield 1.36 grams of A-3-OXO-7LXZl70t-dlm6thyl- 17,6-hydroxy-l6-methylene-estrene which, afterfurther purification, melts at l99.5200.5 C. Optical rotation:

[oc] =42 (c.=0.483 in chloroform).

Infrared spectrum bands (methylene chloride) at 2.78, 6.00 and 6.1810.

The starting material may be prepared as follows:

A solution of 15 grams of A -3-oxo-7a-methyl-l7l3- acetoxy-estrene in150 ml. of isopropenyl acetate and 0.15 ml. of sulphuric acid is boiledfor one hour; 16 ml. of solvent are then distilled off and the batchagain boiled for one hour. The reaction mixture is then treated with 1.5grams of sodium acetate, evaporated in vacuo, the residue taken up inmethylene chloride, the solution washed with water, dried and evaporatedin vacuo. To the suspension of the resulting crude enol acetate in 1litre of alcohol of 95% strength a solution of 6.75 grams of sodiumboron hydride in 135 ml. of alcohol of 70% strength is added withstirring. After two hours and twenty minutes, the mixture is slowlytreated with 12 ml. of glacial acetic acid while being cooled with ice,highly concentrated in vacuo, diluted with water and extracted withmethylene chloride. The organic solutions are washed with water, driedand evaporated in vacuo and the residue is chromatographed on 750 gramsof alumina (activity II). The crystalline fractions eluted with benzeneare recrystallized from a mixture of ether and pentane to yield 7.56grams of A -3fl-hydroxy-7a-methyl- 17fl-acetoxy-estrene. The compoundshows different melting points. The highest is at 134.5l36 C. Opticalro-. tation: [a] =69 (c.=0.558 in chloroform). Infrared spectrum bands(methylene chloride) at 2.77, 2.79 and 8.09,:1.

The fractions obtained with a mixture of benzene and ethyl acetate (1:1)are recrystallized from a mixture of methylene chloride and ether toyield 400 mg. of A 36-1713-dihydroxy-7a-methyl-estrene which, afterbeing recrystallized, melts at 199.5202.5 C. Infrared spectrum bands(Nujol) at 3.05 4.

0.025 ml. of phosphorus oxychloride is added to a solution of 1.2 gramsof the resulting A -3[3hydroxy-7etmethyl-17fl-acetoxy-estrene in 6 ml.of tetrahydrofuran and 6 ml. of dihydropyrane, with stirring, and thebatch is allowed to stand for one and three-quarter hours at roomtemperature. After the addition of 100 ml. of sodium bicarbonatesolution of 2% strength and extraction with methylene chloride, theorganic solutions are washed with water, dried and evaporated in vacuo.To remove the last traces of dihydropyrane, the residue is dissolved inbenzene and the solution again evaporated in vacuo. Crystallization froma mixture of ether and pentane, and from methanol, yields a total of1.22 grams of the tetrahydropyranyl ether of A-3fi-hydroxy-7otmethyl-175-acetoxy-estrene as a mixture ofstereoisomers.

The mixture of 1 gram of the so-obtained tetrahydropyranyl ether and 50ml. of a 5% solution of potassium hydroxide in methanol is stirredovernight at room temperature and then heated for one hour at 60 C. 2.4ml. of glacial acetic acid are then added, the reaction mixtureevaporated in vacuo and, after the addition of water, extracted severaltimes with methylene chloride. The residue of the organic solutions,which have been dried and evaporated in vacuo, is the crudeB-tretrahydropyranyl ether of A -3fi:17fl-dihydroxy-7u-methyl-estrene,and is added together with ml. of pyridine, while being stirred andcooled with ice, to a mixture of 1 gram of chromium trioxide and 10 ml.of pyridine. After being stirred for 21 hours at room temperature, thereaction mixture is diluted with water and extracted several times withbenzene. The extract is washed with water, dried and evaporated invacuo, and the residue, in a benezene solution, is filtered through 3grams of alumina (activity III) while being rinsed with 500 ml. ofbenzene. The evaporation residue of the filtrate is recrystallized froma mixture of methylene chloride, ether and pentane to yield 730 mg. oftetrahydropyranyl ether of A -3 3- hydroxy-7a-methyl-17-oxo-estrenemelting at 151.5- 153.5 C. Infrared spectrum bands (methylene chloride)at 5 .7611

A mixture of 4.28 grams of the so-obtained tetrahydropyranyl ether and60 ml. of acetic acid of strength is placed in a bath of C., thenevaporated in vacuo, the residue dissolved in xylene, the solution againevaporated in vacuo, and this operation is repeated once. The residue isfiltered in a benzene solution through 18 grams of alumina (activity II)while being rinsed with 2 litres of benzene. The evaporation residue ofthe filtrate is recrystallized from a mixture of ether and pentane toyield 2.8 grams of A -3B-hydroxy-7amethyl-l7-oxo-estrene melting at140.5142.5 C. Optical rotation: [a] =-3 (c.=0.604 in chloroform).Infrared spectrum bands (methylene chloride) at 2.77, 2.89 and 5.76;.

A mixture of 3 grams of A -3p-hydroxy-7a-methyl- 17-oxo-estrene, 1.8grams of formaldehyde, 30 ml. of

isoamyl alcohol and 6 grams of dimethylamine hydrochloride is boiled for2 hours in a current of nitrogen; the reaction mixture is then cooled,diluted with water and extracted with ether. The extract is washed withwater, dried and evaporated in vacuo, and the residue is heated with 40ml. of pyridine and 40 ml. of acetic anhydride for two hours at 100 C.in a current of nitrogen. The mixture is evaporated in vacuo, theresidue dissolved in xylene, the solution evaporated in vacuo and thewhole operation is repeated once. The residue is chromatographed on 90grams of alumina (activity II), and the fractions, eluted with a mixtureof benzene and petroleum ether (1:4), are recrystallized from a mixtureof ether and pentane to yield 2.25 grams of A -3B-acetoxy-7a-methyl-16-methylene-17-0xo-estrene. Infrared spectrum bands methylenechloride at 5.79, 6.10 and 8.10

Example 4 To a methyl magnesium bromide solution, prepared byintroducing methyl bromide into a mixture of 9 grams of magnesium andml. of ether, there are added, with stirring and cooling with a mixtureof ice and methanol, first 270 ml. of absolute tetrahydrofuran and, thenslowly and with further cooling, a solution of 3.36 grams of A-3-oxo-16-methylene-17a-ethinyl 17B-hydroxyestradiene and 240 mg. ofcupper acetate in ml. of tetrahydrofuran while rinsing with 65 ml. oftetrahydrofuran. The reaction mixture is stirred for 2 /2 hours in acurrent of nitrogen at room temperature, 220 ml. of saturated ammoniumchloride solution are added dropwise while cooling thoroughly and then110 ml. of water. The batch is then extracted twice with benzene, theextract washed with saturated ammonium chloride solution, dried andevaporated in vacuo. The residue is chromatogra-phed on 100 grams ofalumina (activity II) and the crystalline fractions, eluted with benzeneand benzene-l-ethyl acetate (19:1), are recrystallized from methylenechloride-l-ether +petroleum ether to yield 990 mg. of A-3oxo-7a-methyl-l6-methylene-17a-ethyiny l-17fl-hydroxy-estrene which,after further recrystallization, melts at 19l-196.5 C. Optical rotation:[a] =+1 (c.-=0.536 in chloroform). e ,,=16450. Infrared spectrum bands(methylene chloride) at 2.78, 3.02, 6.00 and 6.18 1.

The starting material may be prepared as follows:

A solution of 35.34 grams of A -3-ethoxy-17-oxoestradiene and 177 gramsof oxalic acid dimet hyl ester in 290 ml. of benzene is added withstirring to amixture of 43 grams of 50% sodium hydride in oiland 180 ml.of benzene in a current of nitrogen, the batch being rinsed with a totalof ml. of benzene. The reaction solution is stirred for 44 hours at abath temperature of 30 C. and then slowly treated with a mixture of 57.6ml. of glacial acetic acid and 325 ml. of ether while being cooled withice. An hour later, 360 ml. of water are added, the batch is extractedwith benzene and the organic solution washed with water. The benzenesolution is dried and evaporated in vacuo, the residue treed in a highvacuum from excess oxalic acid dimethyl ester first, at a bathtemperature of 30 C., and then at a temperature of 60 C. The resultingcrude crystalline condensation product is dissolved in 1.4 litres ofmethanol and the solution stirred for 30 minutes at room temperatureafter the addition of 462 ml. of formaldehyde solution of 37% strength.

In the course of 60 minutes a solution of 80.4 grams of potassiumcarbonate in 720 ml. of water is added dropwise. After a further 90minutes the reaction mixture is extracted with methylene chloride,washed with water and evaporated in vacuo. The residue is dissolved in amixture of benzene and petroleum ether (1:4) and filtered through 420grams of alumina (activity II) while being rinsed with 4 litres of thesame mixture. The filtrate is evaporated and ether and pentane are addedto the residue, to yield 8.67 grams of A-3-ethoxy-16-methylene-17-oxo-estradiene which has an unsharp meltingpoint. e ,,=2600. Infrared spectrum bands (methylene chloride) at 5.78,6.07 and 6.14 t.

20 grams of lithium acetylide ethylenediamine addition compound areadded-to a solution of 8.67 grams of the above obtained methylenecompound in 43 ml. of toluene and 128 ml. of dimethyl sulphoxide withgentle cooling; the batch is stirred for two hours at room temperaturein a current of nitrogen. 86 grams of ammonium chloride are addedcautiously to the reaction mixture while cooling with a mixture of iceand methanol; water is then added and the batch extracted with benzeneand methylene chloride. The organic phases are washed with water, dried,evaporated in vacuo, and the residue chromatographed on 255 grams ofalumina (activity II). The crystalline fractions eluted with benzene arecombined, evaporated and the residue treated with ether, to yield 5.58grams of A -3-ethoxy 16 -methylene-17a-ethinyl- 17,8-hydroxy-estradienemelting at 215-2l9.5 C.; the product is processed immediately.

3.36 grams of bromosuccinimide and 2.7 ml. of glacial acetic acid areadded with stirring to a mixture of 5.2 grams of the so obtained ethinylcompound, 230 ml. of acetone and 2.3 grams of sodium acetate in ml. ofwater at -10 C. The reaction mixture is stirred for 3 hours while beingcooled with a mixture of ice and sodium chloride, and is then treatedwith a solution of 3.8 grams of potassium iodide in 75 ml. of water andthen with a solution of 6.2 grams of sodium thiosulphate in 75 ml. ofwater. The batch is extracted three times with benzene, the extractwashed with dilute sodium chloride solution, dried and evaporated invacuo with the addition of 10 ml. of dirnethylformamide at 40 C. bathtemperature. The residue is dissolved in 160 ml. of dimethylformamideand treated, with stirring in a current of nitrogen, with 9.2 grams oflithium carbonate and 9.2 grams of lithium bromide while being rinsedwith 30 ml. of dimethylformamide. The mixture is stirred for 14 hours ata bath temperature of 100 C., cooled, and then poured on to water and 20ml. of glacial acetic acid, and extracted three times with methylenechloride. The organic solution is washed with water, dried, evaporatedin vacuo and any remaining dimethyl formamide distilled off in a highvacuum. The residue is filtered in a benzene solution through 50 gramsof alumina (activity II) and rinsed with 1.5 litres of a mixture ofbenzene and ethyl acetate (9:1). The filtrate is evaporated and theresidue recrystallized from a mixture of methylene chloride and ether toyield 3.36 grams of A-3-oxol6-methylene-l7aethinyl-l7B-hydroxy-estradiene which after furtherrecrystallization melts at 197.5l98.5 C. Optical rotation: [oc] =4O(c.=0.433 in chloroform). e ,,:27200. Infrared spectrum bands (methylenechloride) at 2.80, 3.03, 6.04, 6.18 and 632 What is claimed is:

1. Methylene-steroids of the formula LCI'IQ in which R stands for amember selected from the group consisting of hydrogen and 0x0, R tor amember selected from the group consisting of hydroxy, acyloxy ofcarboxylic acids with up to 20 carbon atoms, tetrahydropyranyloxy loweralkoxy, lower :alkoxy-lower alkoxy, lower a alkoxy-cycloalkoxy in whichcycloalkyl has 5 to 6 ring carbon atoms, lower a-alkenyloxy, lowera-cycloalkenyloxy in which cycloalkenyl has 5 to 6 ring carbon atoms,lower a-hydroxy-B-halogenalkoxy, and lower alkanoyloxy-fl-halogen-loweralkoxy and R for a member selected from the group consisting of hydrogenand a lower aliphatic hydrocarbon radical.

2. Methylene-estrenes of the formula ---OHs in which R stands foramember selected from the group consisting of hydroxy and acyloxy ofcarboxylic acids with up to 20 carbon atoms and R for a member selectedfrom the group consisting of lower alkyl, lower alkenyl and loweralkyny-l.

3. The 3oxo-derivatives of the compounds claimed in claim 2.

4. A -7oz,17a-dirnethyl-l6-methylene hydroxy-estrene.

5. A -7a-methyl-16-methylene 17a ethinyl 17fi-hydroxy-es-trene.

6. A -3-oxo-'7a,17a-dimethyl l6 methylene 17,8-hydroxy-estrene.

7. A -3-oxo-7ot-methyl-l6-methylene-17u ethinyl 17B- hydroxy-estrene.

References Cited by the Examiner UNITED STATES PATENTS 3,117,060 l/l964Bruckner et al. 167-74 LEWIS GOTTS, Primaryt Examiner.

ELBERT L. ROBERTS, Assistant Examiner.

1. METHYLENE-STERIODS OF THE FORMULA